The Cep57-pericentrin module organizes PCM expansion and centriole engagement

Koki Watanabe,Mikiko Takahashi,Kei K Ito,Daisuke Takao,Daiju Kitagawa

doi:10.1038/s41467-019-08862-2

Abstract

Centriole duplication occurs once per cell cycle to ensure robust formation of bipolar spindles and chromosome segregation. Each newly-formed daughter centriole remains connected to its mother centriole until late mitosis. The disengagement of the centriole pair is required for centriole duplication. However, the mechanisms underlying centriole engagement remain poorly understood. Here, we show that Cep57 is required for pericentriolar material (PCM) organization that regulates centriole engagement. Depletion of Cep57 causes PCM disorganization and precocious centriole disengagement during mitosis. The disengaged daughter centrioles acquire ectopic microtubule-organizing-center activity, which results in chromosome mis-segregation. Similar defects are observed in mosaic variegated aneuploidy syndrome patient cells with cep57 mutations. We also find that Cep57 binds to the well-conserved PACT domain of pericentrin. Microcephaly osteodysplastic primordial dwarfism disease pericentrin mutations impair the Cep57-pericentrin interaction and lead to PCM disorganization. Together, our work demonstrates that Cep57 provides a critical interface between the centriole core and PCM.

Highlights

Centriole duplication occurs once per cell cycle to ensure robust formation of bipolar spindles and chromosome segregation
This could be due to unequal distribution of centrioles (UDC) as was the case of centrosomal protein of 57 kDa (Cep57)-depleted cells. These findings strongly suggest that both Cep[57] depletion and cep[57] mutations in mosaic variegated aneuploidy (MVA) patients cause pericentriolar material (PCM) disorganization and precocious centriole disengagement in mitosis, which results in chromosomal segregation errors and aneuploidy (Fig. 3i)
Given that the cleavage of PCNT, a major PCM component, by separase is required for mitotic centriole disengagement[9,10], and the fact that, among major PCM components that we tested, depletion of PCNT only caused precocious centriole disengagement in early mitosis (Supplementary Fig. 6a, b), we examined whether Cep[57] physically interacts with PCNT

Summary

Introduction

Centriole duplication occurs once per cell cycle to ensure robust formation of bipolar spindles and chromosome segregation. The centrosomes act as MTOCs to ensure the robust formation of mitotic bipolar spindle and proper chromosome segregation At this stage, surrounding PCM drastically expands and acquires MTOC activity. Pericentrin (PCNT, known as kendrin), a PCM component, is known to be a critical substrate cleaved by separase for centriole disengagement[9,10] This cleavage event in mitosis is necessary for timely centriole disengagement and for licensing a new round of centriole duplication in the cell cycle. It has been recently reported that Cep[57] regulates the loading of spindle assembly checkpoint proteins, the Mad1–Mad[2] complex, at kinetochores for timely chromosome segregation in human cells[21]. It is not clear whether its functional homologs in other species function in a similar fashion

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Results

Conclusion